Method of curbing appetite with 1-phenoxy-2-amino-propane



of Germany No Drawing. Filed July 10, 1962, Ser. No. 208,917 Claims priority, application Great Britain, July 31, 1961,

2 Claims. to]. 167-55 This invention relates to appetite-curbing compositions as well as to a method for curbing the appetite.

More particularly, the present invention relates to ap petite-curbing compositions comprising l-phenoxy-Z- amino-propane or a non-toxic, pharmacologically acceptable acid addition salt thereof as an active ingredient, and to a method of curbing the appetite by administering l-phenoxy-2-amino-propane or a non-toxic acid addition salt thereof.

Various compounds which are similar in structure to l-phenoxy-2-amino-propane have been suggested and tested as appetite-depressants; for instance, 1-phenyl-2- amino-propane (amphetamine) and l-phenyl-Z-diethylamino-l-propanone (T enuate). However, these compounds exhibit a number of undesirable side-effects, notably excessive stimulation of the central nervous system. In many cases, therefore, these compounds are contraindicated.

It is an object of the present invention to provide pharmaceutical compositions with eifective appetite-depressant properties, but susbtantially free from undesirable United States Patent side-effects, notably free from stimulating efiects on the 7 central nervous system.

It is another object of the present invention to provide a method of producing anorexia without concurrent stimulation of the central nervous system.

Still other objects and advantages of the present invention will become apparent as the description thereof proceeds.

We have discovered that anorexia is produced, that is, the desire for food intake is eifectively depressed, Without concurrent stimulation of the central nervous system, by administering per os or parenterally from 20 to 100 mgm., preferably to 50 mgm., of a compound selected from the group consisting of 1-phenoXy-2-amino-propane of the formula @o-onrm cna and its non-toxic, pharmacologically acceptable acid addition salts.

In order to demonstrate the effective appetite-curbing activity of l-phenoxy-Z-amino-propane and its non-toxic acid addition salts as Well as their surprisingly low central nervous system stimulating activity, certain standard pharmacological tests were performed wherein the compounds according to the present invention were also subjected to comparison with structurally related compounds having appetite-depressant properties.

First, the dose of each compound in question which reduces the food intake of rats to 50% of normal was determined after subcutaneous and peroral administration.

3,198,701 Patented Aug. 3, 1955 ice For this purpose, varying amounts of each compound in question were administered both subcutaneously and perorally to from 2 to 6 groups of 6 animals each. The amount of food intake per unit of time was measured after each administration and was compared to the food intake rate of an untreated control group. The reduction of the food intake rate, if any, after administration of the compounds in question as compared with the normal rate was expressed in terms of percentage reduction, and the values were recorded on a graph. By interpolation, the amount of each compound which reduces the food intake rate by 5% (ED was graphically determined. The followingvalues were obtained:

Thereafter, each of the compounds in question was investigated for its stimulating effect upon the central nervous system of laboratory mice, as indicated by the spontaneously motoricity. For this purpose, varying amounts of the compounds were injected subcutaneously into separate groups of adult white mice. After each administration the number of animals showing motorial excitation were counted, and the value was recorded on a graph. After a sufiicient number of values had been obtained, the dose at which of the animals showed noticeable motorial excitation (ED was calculated for each compound by the method of Karber (Arch. exp. Path. Pharmakol, vol. 162, pages 480 (1931)).

- The following results were obtained:

An examination of the values tabulated in Tables I and II above shows that'while l-phenoxy-2-amino-pro-' pane is only about to A; as e'fiective as an appetite depressant as lphenyl-2-amino-propane, its central nerv ous system stimulating activity is only about 4 that of l-phenyl-2-amino-propane. In other words, even though the dose of lphenoXy-2-amino-propane needed to produce an equal appetite-depressant effect is 7 to 8 times greater than that of l-phenyl-Z-arnino-propane, the central nervous system stimulating effect of such a dose of 1-phenoxy-2-amino-propane is still only about /5 that of l-phenyl-Z-amino-propane.

Similarly, while Table I shows that l-phenoxy-Z-aminopropane is somewhat less effective as an appetite-depressant than l-phenyl-Z-diethyl-amino-l-propanone, Table H shows quite clearly that its central nervous system stimulating activity is only about one-half thatv of l-phenyl-Z- diethylamino-l-propanoue.

TABLE III Ratio: Compound ED Table II EDW Table I l-phenyl-2amino-propane 1-phenyl-2-diethylamino-l-propanone 1-phen0xy-2-ami11o-propane These values show that the ratio for l-phenoxy-Z- amino-propane is more than times as great as that for Amphetamine and about 1.5 times as favorable as that for Tenuate.

When the motorial excitation of rats was studied with the aid of the vibrating cage method, the low central nervous system stimulating activity of l-phenoxy-2-aminopropane was even more clearly demonstrated. The vibrating cage was mounted in such a way that only oscillations of substantial size were counted; that is, substantially only whole-body movements, exclusive of cleaning and nibbling, of the animals in the cage were taken into consideration. Each substantial oscillation caused the cage to touch a contact element, thereby closing an electrical circuit. The number of electrical impulses thus created was recorded over a period of five to six hours by means of an electronic counting device. The sensitivity and the natural period of oscillation of the cage were continuously controlled by means of a standard pendulum.

The tests were carried out on groups of six adult rats. In order to obtain a control value, groups of six untreated rats were placed into the cage and the natural motility of the animals over a period of a whole day was observed and recorded in terms of number of contacts per hour. The average control value thus obtained was 402 contacts per hour. Thereafter, varying doses each of the compounds under consideration were administered to separate groups of rats by subcutaneous injection, and the animals were placed into the vibrating cage. The number of electrical contacts was counted over a period of five to six hours and was recorded on a graph in terms of contacts per hour. From this graph, the dose of each compound which produces 5000 contacts per hour was calculated (ED The following table shows the values obtained:

TABLE IV Compound (racemic hydrochloride) ED u.

mgm./kg.

1-phenyl-2-amino-propane 0. 84 l-phenyl-Z-diethylamino-l-propanone 5. 2

1-phenoxy-2-aminc-propane 1 At doses up to 60 mgmJkg. the number of contacts per hour was only 1327.

4% TABLE V Compound (racemic hydrochloride) EDmT,

mgmJkg.

Lphenyl-2-amino-propane 0. 6 l-phenyl-2-diethyl-amino-l-propanone 3. 5 1-phenoxy-2-aminopropane 60. U

The toxicity of 1-phenoxy-2amino-propane is very low. The subcutaneous LD in mice is 235 mgm./kg. and the peroral LD in mice is 520 mgm. kg.

1-phenoxy-Z-amino-propane is a known compound. It may be prepared, for example, by catalytic hydrogenation of the oxime of 2-phenoxy-acetone in the presence of a nickel catalyst. At room temperature it is a colorless oil. Its hydrochloride has a melting point of 147148 C. (Hurd and Perletz, J.A.C.S., 68, 38-40).

In addition to the hydrochloride, other non-toxic, pharmacologically acceptable acid addition salts of 1-phenox 2-amino propane are the sulfate, bromide, tartrate, citrate, succinate, phosphate, nitrate, acetate, propionate, butyrate, valerate, oxalate, malonate, maleate, fumarate, lactate, malate, benzoate, phthalate, cinnamate, salicylate, nicotinate, Z-furoate, 8-chlorotheophyllinate and the like.

Dosage unit compositions for oral administration are particularly preferred and may be in liquid, syrupy or solid form. Thus, for example, the compounds according to the invention may be compounded with an aqueous or oily medium in the form of suspensions, emulsions, syrups or like formulation, said formulation also containing, if desired, such inert additives as suspending agents, dispersing agents, flavoring agents and/or sweetening agents. One may also with advantage prepare solid formulations, for example, powders or granulates. Preferably, however, the compositions are formulated as solid dosage units for oral administration, such as tablets, capsules, pills or coated pills, in which the compounds are in association with a solid carrier. In particular, one may thus provide tablets containing the active compounds, in which the compounds are in association with suitable tablet-forming additives, for example with sugars, such as lactose or sucrose, finely divided silicic acid, talcum lubricants, such as magnesium stearate or glycerol, and/or binders, such as starch, alginic acid, polyvinyl pyrrolidone or gelatin. Each dosage unit preferably contains 20100 mgm., advantageously 30-5 0 mgm., of l-phenoxy-Z-amimopropane or a non-toxic, pharmacologically acceptable salt thereof.

In compositions for rectal administration the pharmaceutical carrier generally includes a suppository base, such as a glyceride or cocoa butter.

The following examples illustrate typical appetite-curbing dosage unit compositions according to the present invention. It should be understood, however, that the present invention is not limited to these particular examples. The parts are parts by weight unless otherwise specified:

Example I The tablets are compounded from the following ingredients:

The l-phenoxy-Z-aminopropane salt, the lactose and part of the corn starch and silicic acid are mixed together and the mixture is granulated with a 10% solution of the gelatin. The granulate is then passed through a screen of 1.5 min. mesh, dried for about 12 hours at 45 C. and the dried granulate is again passed through a screen of 83 1.5 mm. mesh. The granulate is then mixed with the rest of the corn starch and silicic acid and with the magnesium stearate and the mixture is compressed into tablets of 200 mgm. weight each.

Example II The tablets are compounded from the following ingredients:

The 1-phenoXy-2-arnino-propane is evenly dispersed in a melt of the caster wax and the molten mixture is stirred until cool. The solidified melt is broken down to a particle size of 1.5 mm. and is mixed with a granulate of the lactose and corn starch and with the talcum and magnesium stearate. It is finally compressed into tablets of 220 mgm. each.

Example HL-Powder The powder is compounded from the following ingredients:

Parts 1-phenoxy-2-amino-propane-HC1 30 Lactose, q.s. ad 500 The active material is homogenized with the lactose and the mixture is filled into powder-capsules containing 500 mgm. of the mixture.

Example I V.-Capsulcs The contents of the capsules are compounded from the following ingredients:

Parts 1-phenoxy-2-amino-propane-HC1 30 Lactose, q.s. ad 260 The active substance is homogenized with the lactose and the mixture is filled into gelatine capsules containing 260 mgm. of the mixture.

Obviously, l-phenoxy-Z-arnino-propane or any of the other non-toxic, pharmacologically acceptable acid addition salts may be substituted in the above illustrated compositions for the hydrochloride used therein.

While We have illustrated our invention with the aid of certain specific embodiments thereof, it will be readily apparent to those skilled in the art that the invention is not limited to these embodiments and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

We claim:

1. The method of curbing the appetite of Warm-blooded animals without, at the same time, stimulating the central nervous system of said animals, which comprises orally administering to said animals from 20 to 100 mgm. of a compound selected from the--group consisting of 1- phenoXy-2-amino-propane and its non-toxic, pharmacologically acceptable acid addition salts.

2. The method of curbing the appetite of warm-blooded animals Without, at the same time, stimulating the central nervous system of said animals, which comprises orally administering to said animals from 20 to 100 mgm. of 1-phenoXy-2-an1ino-propane hydrochloride.

JULIAN S. LEVITT, Primary Examiner. FRANK CACCIAPAGLIA, JR., LEWIS GOTTS,

Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,198,701 August 3, 1965 Karl Zeile et al.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, line 33, for "susbtantially" read substantially column 2, line 12, for "5%" read 50% line 36, for "pages" read page Signed and sealed this 25th day of January 1966.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. THE METHOD OF CURBING THE APPETITE OF WARM-BLOODED ANIMALS WITHOUT, AT THE SAME TIME, STIMULATING THE CENTRAL NERVOUS SYSTEM OF SAID ANIMALS, WHICH COMPRISES ORALLY ADMINISTERING TO SAID ANIMALS FROM 20 TO 100 MGM. OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 1PHENOXY-2-AMINO-PROPANE AND ITS NON-TOXIC, PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS. 